Tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives which are promising therapeutic agents for diabetic complications showing a potent aldose reductase inhibitory activity are disclosed in the literature (for example, see JP-A-5-186472; and J. Med. Chem., 1998, 41, p. 4118 to 4129). Also Ranirestat [AS-3201; (3R)-2′-(4-bromo-2-fluorobenzyl)spiro[pyrrolidin-3,4′(1′H)-pyrrolo[1,2-a]pyra zine]-1′,2,3′,5(2H′)-tetraone] selected among these derivatives has been developed clinically. 3-Amino-2,5-dioxopyrrolidine-3-carboxylates are disclosed as the intermediate suitable to prepare these derivatives on the industrial scale in the literature (for example, see JP-A-6-192222), and the process for preparing the same is also disclosed in the literatures (for example, JP-A-5-186472, JP-A-6-192222 and J. Med. Chem., 1998, 41, p. 4118 to 4129 as aforementioned). The summary of the process for preparing the same is illustrated in following Scheme 1.
wherein R1 and R6 are a protecting group for a carboxyl group, R4 is a group cleavable by hydrogenolysis or a tert-butoxycarbonyl group, R5 is a tert-butyl group or a group cleavable by hydrolysis or hydrogenolysis.
In the above route A and route B, there is a step for a ring closure reaction of the 3-cyanopropionic acid ester moiety using hydrogen peroxide and base to form 2,5-dioxopyrrolidine ring and then it is difficult for this step to control the reaction temperature. This is caused by the fact that this step is an exothermic reaction and thus often happens to foam violently. Therefore it is necessary to proceed with this step while cooling. But excess cooling makes the progress of the reaction insufficient to complete and results in lowering the yield and the purity of the desired product. On the other hand, insufficient cooling results in forming a large amount of side products and thus similarly as above, results in lowering the yield and the purity of the desired product. Therefore it is necessary to improve this step. Also relatively high level of hydrogen peroxide used in this step is dangerous and thus there is a risk of decomposing violently in the reaction. Therefore it is also desirous of a method for avoiding the use thereof.
The route C is the process without use of hydrogen peroxide. But it is desirous of a more economically advantageous method since this route requires a large number of steps in total compared to the route A and the process shown in Scheme 2 mentioned below.
A literature describes a preparation of 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide by reacting diethyl benzyloxycarbonylaminomalonate with sodium hydride and bromoacetamide in the examples (see JP-A-6-192222). But this process is not preferred for the industrial scale preparation because of low yield (36.5%) as well as evolution of hydrogen gas in the course of the reaction with sodium hydride.